The overall goal of the proposed studies is to determine the mechanisms by which the availability of choline and folic acid during the prenatal period modifies brain structure and function in development, adulthood and old age. Our major premise is that the development of the brain during critical periods in embryogenesis is sensitive to changes in maternal diet, and specifically, is influenced by changes in the intake of choline and folic acid. We found that rats treated with choline during specific perinatal periods inhibited improved memory function which lasted throughout their lifespan, i.e. supplementation with choline in development prevented age-related deterioration in learning and memory. Moreover, variations in maternal choline intake during the second half of pregnancy caused biochemical, structural, and electrophysiological changes in the brains of the offspring. We also found that memory performance in rats was improved by prenatal supplementation with folic acid. The proposed studies will be conducted using a unified experimental design common to all projects. Dr. Blusztajn will determine the molecular mechanisms involved in the brain reorganization that is governed by choline and folate availability by studying signal transduction pathways and developmental patterns of gene expression in brain. Dr. Swartzwelder will measure synaptic function and plasticity (long-term potentiation in hippocampus of rats exposed to varying levels of choline or folate in utero. Dr. Meck will examine age-related changes in conditioned stimulus processing (attention) as a function of the prenatal availability of choline and folate. Dr. Williams will determine if supplementation with folate in early development leads to life long changes in spatial memory, brain anatomy, and neurochemistry, as has been documented for choline supplementation, and will investigate whether choline supplementation with folate in early development leads to lifelong changes in spatial memory, brain anatomy, and neurochemistry, as has been documented for choline supplementation, and will investigate whether choline supplementation either prenatal or across the lifespan ameliorates behavioral, anatomical, and biochemical deficits seen in mice lacking the gene for apolipoprotein E-a molecular involved in the transport of phosphatidylcholine within brain. Dr. Zeisel will study metabolic interrelationships between folate and choline in order to determine if they share a common mechanism of action on brain organization. He will determine the effects of choline and folate on patterns of fetal brain cell division and apoptosis, and will investigate the mechanism by which choline deficiency causes apoptosis. Dr. Kowall will provide neuroanatomy core services for the five projects. The ultimate goal of our studies is to related our results to age-related changes in memory in humans, and to develop perinatal nutritional strategies which will benefit people.